Despite the phenomenal success of antibiotics and vaccines, infectious diseases remain one of the leading cause of death worldwide. The emergence of multidrug-resistant bacteria has created a situation in which there are few or no options for treating certain infections. The intrinsic limitations of existing vaccines (cost, safety, shelf-life, etc.) and the current trend in major pharmaceutical companies to abandon antibiotic and vaccine development programs create an alarming situation with potentially catastrophic public health consequences. The radical solution for this global biomedical problem and the goal of the proposed research is the development of conceptually new approaches to prevent and treat infectious diseases. One general strategy is to create a new type of fully synthetic antimicrobials for which it would be intrinsically difficult for bacteria to develop resistance. At least one prototype, a chemical platform based on 5-aminonaphthalenesulfonamides (ANSA), has been designed in our laboratory as a proof-of-principle. Unlike the majority of antibiotics that target individual macromolecules, ANSA compounds irreversibly damage various proteins at once, thus rapidly killing a target cell. This process requires nitric oxide (NO). Endogenous NO is sufficient to render bacteria susceptible to ANSA, and exogenous NO (e.g. from macrophages) further stimulates the bactericidal effect. The combinatorial selection of the most potent ANSA and related compounds will be carried out to define the specificity for different pathogenic bacterial species. The second general approach involves creating probiotic-based vaccines. Probiotics are live bacteria that colonize or temporarily survive in the host, while conferring beneficial effect on its health. Probiotics that stably and controllably secrete or display antigens for various pathogens could effectively serve as self-sustaining vaccines. As a proof-of-principle we will engineer probiotic strains that upon oral administration to mice will induce a proper immune response rendering animals resistant to otherwise lethal infections.